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Clinical description, molecular delineation and genotype–phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients
  1. Elena Martinez-Cayuelas1,
  2. Fiona Blanco-Kelly2,3,
  3. Fermina Lopez-Grondona2,
  4. Saoud Tahsin Swafiri2,3,
  5. Rosario Lopez-Rodriguez2,4,
  6. Rebeca Losada-Del Pozo1,
  7. Ignacio Mahillo-Fernandez5,
  8. Beatriz Moreno1,
  9. Maria Rodrigo-Moreno1,
  10. Didac Casas-Alba6,
  11. Aitor Lopez-Gonzalez6,
  12. Sixto García-Miñaúr3,7,
  13. Maria Ángeles Mori3,7,
  14. Marta Pacio-Minguez7,
  15. Emi Rikeros-Orozco7,
  16. Fernando Santos-Simarro3,7,
  17. Jaime Cruz-Rojo8,9,
  18. Juan Francisco Quesada-Espinosa8,10,
  19. Maria Teresa Sanchez-Calvin8,10,
  20. Jaime Sanchez-del Pozo8,9,
  21. Raquel Bernado Fonz11,
  22. Maria Isidoro-Garcia12,
  23. Irene Ruiz-Ayucar13,
  24. Maria Isabel Alvarez-Mora14,
  25. Raquel Blanco-Lago15,
  26. Begoña De Azua16,
  27. Jesus Eiris17,
  28. Juan Jose Garcia-Peñas18,
  29. Belen Gil-Fournier19,
  30. Carmen Gomez-Lado17,
  31. Nadia Irazabal20,
  32. Vanessa Lopez-Gonzalez21,
  33. Irene Madrigal3,14,
  34. Ignacio Malaga15,
  35. Beatriz Martinez-Menendez22,
  36. Soraya Ramiro-Leon19,
  37. Maria Garcia-Hoyos23,
  38. Pablo Prieto-Matos13,
  39. Javier Lopez-Pison24,
  40. Sergio Aguilera-Albesa11,
  41. Sara Alvarez23,
  42. Alberto Fernández-Jaén25,
  43. Isabel Llano-Rivas26,
  44. Blanca Gener-Querol26,
  45. Carmen Ayuso2,3,
  46. Ana Arteche-Lopez8,10,
  47. Maria Palomares-Bralo3,7,
  48. Anna Cueto-González27,
  49. Irene Valenzuela27,
  50. Antonio Martinez-Monseny6,
  51. Isabel Lorda-Sanchez2,3,
  52. Berta Almoguera2,3
  1. 1Department of Pediatrics, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain
  2. 2Department of Genetics and Genomics, Hospital Universitario Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain
  3. 3Centro de Investigacion Biomedica en Red de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain
  4. 4School of Pharmacy, Universidad San Pablo CEU. CEU Universities, Madrid, Spain
  5. 5Department of Statistics, Hospital Universitario Fundacion Jimenez Diaz (IIS-FJD), Madrid, Spain
  6. 6Clinical Genetics and Dysmorphology, Department of Genetic and Molecular Medicine, Pediatric Insitute of Rare Diseases (IPER), Hospital Sant Joan de Deu, Barcelona, Spain
  7. 7Medical and Molecular Genetics Institute (INGEMM), Hospital Universitario La Paz, Madrid, Spain
  8. 8Dysmorphology and Genetics Unit (UDISGEN), Hospital Universitario 12 de Octubre, Madrid, Spain
  9. 9Endocrinology Unit, Department of Pediatrics, Hospital Universitario 12 de Octubre, Madrid, Spain
  10. 10Department of Genetics, Hospital Universitario 12 de Octubre, Madrid, Spain
  11. 11Pediatric Neurology Unit, Department of Pediatrics, Navarrabiomed Pediatric Neurology Research Group, Hospital Universitario de Navarra, Pamplona, Spain
  12. 12Department of Biochemistry, Hospital Universitario de Salamanca. IBSAL Universidad de Salamanca, Salamanca, Spain
  13. 13Department of Pediatrics, Hospital Universitario de Salamanca, Salamanca, Spain
  14. 14Department of Biochemistry and Molecular Genetics, IDIBAPS (Institut de Investigacions Biomèdiques August Pi I Sunyer), Hospital Clinic de Barcelona, Barcelona, Spain
  15. 15Pediatric Neurology Unit, Department of Pediatrics, Hospital Universitario Central de Asturias, Oviedo, Spain
  16. 16Department of Pediatrics, Hospital Son Llàtzer, Palma de Mallorca, Spain
  17. 17Department of Pediatric Neurology, Hospital Universitario de Santiago de Compostela, Santiago de Compostela, Spain
  18. 18Pediatric Neurology Unit, Department of Pediatrics, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
  19. 19Department of Genetics, Hospital Universitario de Getafe, Madrid, Spain
  20. 20Department of Pediatrics, Hospital Can Misses, Eivissa, Spain
  21. 21Medical Genetics Unit, Department of Genetics, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain
  22. 22Pediatric Neurology Unit, Department of Neurology, Hospital Universitario de Getafe, Madrid, Spain
  23. 23Genetic Diagnosis Service, NIMGenetics Genomics and Medicine, Madrid, Spain
  24. 24Pediatric Neurology Unit, Department of Pediatrics, Hospital Universitario Miguel Servet, Zaragoza, Spain
  25. 25Department of Pediatric Neurology, Hospital Universitario Quironsalud Madrid, Madrid, Spain
  26. 26Department of Genetics, Hospital Universitario de Cruces. Biocruces Bizcaia Health Research Institute, Bizcaia, Spain
  27. 27Department of Clinical and Molecular Genetics, Vall d'Hebron Research Institute, Hospital Universitario Vall d'Hebron, Barcelona, Spain
  1. Correspondence to Dr Berta Almoguera, Department of Genetics and Genomics, Hospital Universitario Fundacion Jimenez Diaz, Madrid, 28040, Spain; balmoguera{at}


Background KBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been reported. Both loss-of-function sequence variants and large deletions (copy number variations, CNVs) involving ANKRD11 cause KBG syndrome, but no genotype–phenotype correlation has been reported.

Methods 67 patients with KBG syndrome were assessed using a custom phenotypical questionnaire. Manifestations present in >50% of the patients and a ‘phenotypical score’ were used to perform a genotype–phenotype correlation in 340 patients from our cohort and the literature.

Results Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures. 82.8% of the patients had at least one of seven main comorbidities: hearing loss and/or otitis media, visual problems, cryptorchidism, cardiopathy, feeding difficulties and/or seizures. Associations found included a higher phenotypical score in patients with sequence variants compared with CNVs and a higher frequency of triangular face (71.1% vs 42.5% in CNVs). Short stature was more frequent in patients with exon 9 variants (62.5% inside vs 27.8% outside exon 9), and the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants). Presence of macrodontia and comorbidities were associated with larger deletion sizes and hand anomalies with smaller deletions.

Conclusion We present a detailed phenotypical description of KBG syndrome in the largest series reported to date of 67 patients, provide evidence of a genotype–phenotype correlation between some KBG features and specific ANKRD11 variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.

  • Genetics
  • Genetics, Medical
  • Pediatrics
  • Diagnosis

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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  • Contributors EM-C, FB-K, IL-S and BA designed the study. EM-C, FB-K, RL-R, IM-F, IL-S and BA analysed the data. EM-C and BA prepared the manuscript. EM-C, FB-K, FL-G, STS, RL-DP, BM, MR-M, DC-A, AL-G, SG-M, MAM, MP-M, ER-O, FS-S, JC-R, JFQ-E, MTS-C, JS-dP, RB-F, MI-G, IR-A, MIA-M, RB-L, BdA, JE, JJG-P, BG-F, CG-L, NI, VL-G, IMad, IMal, BM-M, SR-L, MG-H, PP-M, JL-P, SA-A, SA, AF-J, IL-R, BG-Q, CA, AA-L, MP-B, AC-G, IV, AM-M and IL-S contributed to the acquisition, analysis and interpretation of the data used in the study. All authors critically reviewed the manuscript, approved the final version and are accountable for all aspects of the work. BA is responsible for the overall content as guarantor and accepts full responsibility for the finished work and/or the conduct of the study, had access to the data, and controlled the decision to publish.

  • Funding Berta Almoguera’s work is supported by a Juan Rodés program (JR17/00020) and a grant from Fondo de Investigaciones Sanitarias (FIS, PI18/01098), funded by Instituto de Salud Carlos III and the European Regional Development Fund (FEDER).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.